Longitudinal Epigenome-Wide Methylation Study of Cognitive Decline and Motor Progression in Parkinson's Disease

Background: DNA methylation studies in Parkinson's disease (PD) thus far have focused on disease susceptibility but not progression. Objective: In this epigenome-wide association study (EWAS), we aim to identify methylation markers associated with faster cognitive decline or motor progression in PD. Methods: We included 232 PD patients from the Parkinson's Environment and Gene follow-up study who provided blood samples at enrolment. Information on cognitive and motor function was collected using the Mini-Mental State Examination (MMSE) and Unified Parkinson's Disease Rating Scale (UPDRS). For EWAS analyses, we used a robust measure of correlation: biweight midcorrelations, t-tests, and Cox proportional hazard models. We also conducted weighted correlation network analysis (WGCNA) to identify CpG modules associated with cognitive decline or motor progression in PD. Results: Among 197 individuals of European ancestry, with our EWAS approach we identified 7 genome-wide significant CpGs associated with a MMSE 4-point decline and 8 CpGs associated with faster motor progression (i.e., rate of UPDRS increase >= 5-point/year). The most interesting CpGs for cognitive decline include cg17445913 in KCNB1 (cor = 0.36, p = 6.85 x 10(-7)) and cg02920897 in DLEU2 (cor = 0.34, p = 3.23 x 10(-6)), while for motor progression it was cg01754178 in PTPRN2 (cor = -0.34, p = 2.07 x 10(-6)). In WGCNA, motor progression related modules were enriched for genes related to neuronal synaptic functions, Wnt signaling pathway, and mitochondrial apoptosis. Conclusions: Our study provides the first epigenetic evidence that differential methylation in genes previously identified as being associated with cognitive impairment, neuronal synaptic function, Wnt signaling pathway, and mitochondrial apoptosis is associated with cognitive and motor progression in PD.